Project Summary. The prevalence of diabetes mellitus (DM) has nearly doubled since 1980. Current population growth rates and aging demographics predict an even more rapid rise in the burden of DM and associated complications in the years to come. Diabetic retinopathy (DR) affects ~30% of diabetics and represents the leading cause of working class blindness in both the industrialized and developing nations. Despite a range of treatment options (i.e. laser photocoagulation, blood-glucose regulation, corticosteroids and anti-vascular endothelial growth factor (VEGF) injections), the ability to address the complex nature of DR remains a significant challenge. Surgical methods are irreversibly destructive and the standard of care (i.e. anti-VEGF therapy) suffers from the requirement of frequent injections, high cost ($1.5 B in 2008-09), limited access in developing countries, and must be administered by healthcare specialists. Therefore, a critical need exists for low-cost, readily accessible, and systemically available DR treatments. Of particular importance is the development of therapies that simultaneously address the inflammatory and neovascularization (NV) events involved in DR etiology. PPAR? agonism has demonstrated promise as a therapeutically viable option to address the major pathological features of diabetic macular edema responsible for vision loss in DR. To date, fenofibrate is the only PPAR? agonist known to cross the blood-ocular barrier and provide protective effects against DME and NV. Fenofibrate however, suffers from low ocular distribution, lack of selectivity between different members of the PPAR family, and dose limiting toxicity, which will limit its use as a DR therapy. The fenofibrate results, however, demonstrate that PPAR? agonists that exhibit improved potency and enhanced ocular distribution have high promise to become a low-cost and orally available therapeutic option for the treatment of DR. Recently, NCI8 was identified from a computational screen as a novel PPAR? agonist and this compound exhibits equipotency and equal efficacy to fenofibrate in vitro and in vivo, respectively. Unlike fenofibrate, however, NCI8 is a selective PPAR? agonist and thus we hypothesize that this chemotype can be rationally optimized into a potent and efficacious small molecule treatment for DR. The objective of this proposal is to conduct iterative structure-activity relationship studies to optimize NCI8 from a hit into viable therapeutic leads. The aims of this proposal will be conducted in parallel and include 1) the synthesis of rationally designed NCI8-inspired derivatives and 2) the assessment of the new derivatives to act as PPAR? agonists in initial in vitro and in vivo assays. Seeking to treat DR with a systemically available small molecule is innovative, as it deviates from all known current therapeutic options. This research is significant as is seeks to provide a widely available DR treatment option that addresses the cost, availability, and administration limitations posed by the current standard of care.